Elements of a Paracrine Tubular Renin-Angiotensin System Along the Entire Nephron

Rohrwasser, Andreas; Morgan, Terry K.; Dillon, Harrison F.; Zhao, Ling; Callaway, Christopher W.; Hillas, Elaine; Zhang, Shuhua; Cheng, Tong; Inagami, Tadashi; Ward, Kenneth; Terreros, Daniel; Lalouel, J.-M.

doi:10.1161/01.hyp.34.6.1265

Cited by 270 publications

(310 citation statements)

References 42 publications

(39 reference statements)

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“…Renin mRNA and protein are expressed in the proximal and connecting tubules, as well as the collecting ducts. 19,[46][47][48][49][50][51][52][53][54] Interestingly, mechanisms for regulating tubular renin seem to be independent of those in the JG cell. 47,48,50,52 Proximal tubular cells express mRNA [54][55][56] and protein 53,57 for ACE and Aogen.…”

Section: Intrarenal Raasmentioning

confidence: 99%

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Feldman

2010

Hypertens Res

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The renin-angiotensin-aldosterone system (RAAS) has a central function in the regulation of blood pressure. Aliskiren, the first direct renin inhibitor to be approved for the treatment of hypertension, blocks the RAAS at its point of activation. As renin inhibition acts at the top of the RAAS cascade, this mechanism has been proposed to offer advantages over existing modes of RAAS blockade. The RAAS is also considered to be a major factor in the pathogenesis of many renal diseases, especially diabetic nephropathy (DN), the main cause of end-stage renal disease. Existing therapies to block the RAAS slow the progression of DN, but they do not halt the disease. Therefore, more effective modes of interventions are needed. Studies to determine the efficacy of aliskiren in human renal disease are in progress. This review summarizes in vivo studies in which the efficacy of aliskiren was tested in experimental models of renal disease, and presents in vitro studies that provide insights into the possible mechanisms by which aliskiren confers renoprotection in animals. These works are discussed in the framework of the intrarenal RAAS and suggest that aliskiren may act by unique renoprotective mechanisms. Keywords: aliskiren; kidney; mechanism; nephropathy; renin INTRODUCTIONThe renin-angiotensin-aldosterone system (RAAS) is an ancient pathway 1 that has evolved into a central mechanism by which mammalian blood pressure (BP) and fluid homeostasis are regulated. Research in this field started with the discovery in 1898 by Tigerstedt and Berman 2 that a renal extract when injected into rabbits induced a rapid increase in systemic BP. Subsequent work over many years established the RAAS as a pivotal contributor to cardiorenal diseases. Hence, inhibitors of the middle and distal portions of the RAAS pathway, angiotensin-converting enzyme (ACE) inhibitors (ACEI) and AT 1 receptor blockers, respectively, have become mainstay therapies for treating hypertension. In 2007, aliskiren, the first direct renin inhibitor (DRI), was approved for the treatment of hypertension. This heralded the therapeutic control of BP by inhibiting the RAAS at its first and rate-limiting step. However, RAAS blockade is also effective for treating renal disease 3-6 and the efficacy of aliskiren for this purpose is currently being investigated. Accordingly, the subject of this review is to summarize the preclinical evidence for renoprotection by aliskiren, and to discuss recently published information on the possible mechanism(s) for these benefits. As it is well recognized that there is a tissue as well as circulating RAAS, 7 the preclinical actions of aliskiren will be discussed in the context of the intrarenal RAAS and the potential for its inhibition by aliskiren.

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Section: Intrarenal Raasmentioning

confidence: 99%

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Feldman

2010

Hypertens Res

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“…Lalouel and colleagues [72,73] have focused on intratubular RAS. Confluent monolayers of conditionally immortalized cells of murine proximal tubules were grown on semipermeable membranes separating apical and basolateral compartments.…”

Section: Angiotensinogenmentioning

confidence: 99%

Renal Renin-Angiotensin System

Ichihara

Kobori

Nishiyama

et al. 2004

Contributions to Nephrology

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The cardinal role of the intrarenal renin-angiotensin system (RAS) in the control of sodium excretion and the pathophysiology of hypertension continues to receive increased attention. In addition to its very powerful vasoconstrictor action, angiotensin (Ang) II exerts important actions on tubular transport function and several recent studies have emphasized the potential importance of actions of angiotensin peptides on receptors localized to the luminal membranes of both proximal and distal nephron segments. Furthermore, a strong case is being developed supporting the importance of local mechanisms regulating the activity of the RAS. This is due to the fact that all components of the RAS are strongly expressed in the kidneys.

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“…Luminal ANG II has been shown to stimulate Na/H exchange activity on the brush border so the sustained proximal tubule ANG II concentrations in these hypertensive models may be responsible for maintained proximal tubule sodium reabsorption rates and thus contribute to the continued ANG II dependent actions on proximal tubule reabsorption rate. A recent study by Rohrwasser et al (61) demonstrated localization of angiotensinogen mRNA and protein in proximal tubules of mice and detected angiotensinogen from the apical side of mouse proximal tubule monolayers. These investigators also detected angiotensinogen in the urine and renin in connecting tubule cells of the distal nephron.…”

Section: Intrarenal Ang II Levels In Hypertensive Ratsmentioning

confidence: 99%

Intrarenal Angiotensin II Augmentation in Angiotensin II Dependent Hypertension.

Navar

Harrison‐Bernard

2000

Hypertens Res

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In several models of angiotensin II (ANG II) dependent hypertension, intrarenal ANG II levels increase to a much greater extent than the circulating levels even though the renal renin levels are decreased. The 2-kidney-l-clip (2K1C) Goldblatt rat model is particularly intriguing because hypertension develops in the presence of an intact kidney which would be expected to maintain sodium balance and protect against hypertension.Although the non-clipped kidney becomes renin depleted, it exhibits enhanced microvascular reactivity and increased tubular fractional sodium reabsorption. content was due to accumulation of circulating ANG II in addition to continued production of endogenous ANG II. The renal accumulation of Va15-ANG II was markedly reduced by concomitant treatment with the AT, receptor blocker, losartan. In addition, we found an unchanged overall ANG II-AT, receptor protein which probably contributes to the maintained ANG II dependent influences. Collectively, the data support the concept that there is internalization of ANG II through an AT, receptor mediated process and that some of the internalized ANG II is protected from degradation. The augmented intrarenal ANG II coupled with sustained levels of AT, receptors contribute to the continued ANG II dependent suppression of renal function and sodium excretion thereby maintaining the hypertension. (Hypertens Res 2000; 23: 291-301)

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Elements of a Paracrine Tubular Renin-Angiotensin System Along the Entire Nephron

Cited by 270 publications

References 42 publications

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

New insights into the renoprotective actions of the renin inhibitor aliskiren in experimental renal disease

Renal Renin-Angiotensin System

Intrarenal Angiotensin II Augmentation in Angiotensin II Dependent Hypertension.

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